Ion channels are proteins that span the lipid bilayer of the cell membrane and provide an aqueous pathway through which specific ions such as Na+, K+, Ca2+ and Cl− can pass (Herbert, 1998). Potassium channels represent the largest and most diverse sub-group of ion channels and they play a central role in regulating the membrane potential and controlling cellular excitability (Armstrong & Hille, 1998). Potassium channels have been categorized into gene families based on their amino acid sequence and their biophysical properties (for nomenclature see Gutman et al., 2003).
Compounds which modulate potassium channels have multiple therapeutic applications in several disease areas including autoimmune, inflammatory, cardiovascular, neuronal, auditory, renal and metabolic mediated diseases (Shieh et al., 2000; Ford et al., 2002, Xie et al, 2004). The potassium channel Kv1.3 is found in a number of tissues including neurons, blood cells, osteoclasts, macrophages, epithelia, and T- and B-lymphocytes. Furthermore, Kv1.3 inhibition has been shown to modulate T-cell function which has implications in many autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, obesity, diabetes and inflammatory bowel disease (Beeton et al., 2006).
Kv1.3 Channel Blockers for Autoimmune Disorders
The role of autoreactive, late-stage, memory TEM cells in the pathogenesis of a variety of autoimmune diseases including psoriasis, rheumatoid arthritis, multiple sclerosis, IBD and others is well established. Activation of TEM cells is followed by substantial up-regulation of Kv1.3 channel expression and, as a result, Kv1.3 becomes the predominant route of potassium efflux from the cell. Thus, selective blockade of Kv1.3 causes membrane depolarisation and inhibition of Ca2+ influx, leading to inhibition of cytokine production and cell proliferation and function. Kv1.3 thus represents a novel therapeutic target of great interest for autoimmune disease control.
T-Cells and Autoimmunity
T-cells are lymphocytes which play a central role in cell mediated immunity. One of the major forms of T-cell is the helper T-cell (TH), also known as CD4+ cells which plays an essential role in the development of autoimmune diseases. Through the production of the cytokine interleukin 2 (IL-2), CD4+ T-cells can create the second main type of T cell known as cytotoxic T-cells (CD8+). Naïve (inactive) CD4+ and CD8+ T-cells express both proteins (CCR7+ CD45RA+) and use the chemokine receptor CCR7 as a key to gain entry into lymph nodes. Within lymph nodes, the naïve T-cells encounter antigen and through an activation process, change into “effector” T-cells that produce cytokines and proliferate. Once the ensuing immune response subsides, most naïve effectors die, but a few differentiate into long-lived central memory cells (TCM). TCM cells, like naïve cells, use CCR7 to home to the lymph nodes to encounter their cognate antigen. Upon antigenic stimulation, TCM cells change into “TCM effector” cells that produce cytokines and proliferate. They too suffer the same fate as naïve effectors, the majority dying after the immune response wanes, leaving a few long-lived survivors for further challenge. Repeated antigenic challenge, as might happen in autoimmune diseases or in chronic infections, causes TCM cells to differentiate into short-lived “effector memory T-cells” (TEM) that lack expression of both CCR7 and CD45RA, and do not need to home to lymph nodes for antigen-induced activation. A subset of CD8+ TEM cells reacquire CD45RA and become CCR7-CD45RA+ TEMRA cells. Upon activation, both CD4+ and CD8+ TEM cells change into TEM effectors that migrate rapidly to sites of inflammation and produce large amounts of the proinflammatory cytokines, interferon-γ (IFN-γ) and tumor necrosis factor α (TNFα). In addition, CD8+ TEM effectors carry large amounts of perforin and are therefore immensely destructive (Wulff et al, 2003, Beeton et al, 2005).
Functional Role of Kv1.3 in T-Cells and Autoimmune Disorders
Human T-cells express two K+ channels, Kv1.3 and IKCa1, that provide the counterbalance cation efflux necessary for the sustained elevation of cytosolic Ca2+ levels required for gene transcription, proliferation and cytokine secretion (Panyi et al, 2004, Chandy et al, 2004). The Kv1.3 and IKCa1 (also known as KCa3.1) channels regulate membrane potential and facilitate Ca2+ signalling in T-lymphocytes. Kv1.3 opens in response to membrane depolarisation and maintains the resting membrane potential (initiation phase), whereas IKCa1 opens in response to an increase in cytosolic Ca2+ and hyperpolarises the membrane potential (Beeton et al, 2001). Selective blockade of K+ channels leads to membrane depolarisation, which in turn inhibits Ca2+ influx and shuts down cytokine production and cell proliferation. Early in vitro studies, using channel blocker toxins, clearly demonstrate that Kv1.3 channels are essential for the synthesis (gene activation) and secretion of the cytokine IL-2 after T-cell activation (Price et al, 1989) and provide a rationale for the potential therapeutic use of inhibitors of this channel in immunological disorders. The role of autoreactive T-cells in the pathogenesis of autoimmune diseases has clearly been demonstrated in animal models. Disease-specific, autoreactive T-cells in several other autoimmune diseases are also reported to exhibit a memory phenotype. Autoreactive TEM cells are also implicated in psoriasis, rheumatoid arthritis, multiple sclerosis, IBD, vitiligo, uveitis, pemphigus, inflammatory myopathies, Hashimito disease, and scleroderma (Beeton et al, 2005). “Late” memory T- and B-cells have been implicated in the disease progression and tissue damage in a number of autoimmune diseases, in transplant rejection and chronic graft-versus-host disease. Modulators of the Kv1.3 channel may allow selective targeting of disease-inducing effector memory T-cells and memory B-cells without compromising the normal immune response and as a result are likely to have a preferred side-affect profile than agents that bring about more general immunosuppression.
The observation that the Kv1.3 blocker margatoxin (MgTX) effectively suppressed the delayed-type hypersensitivity (DTH) response in vivo was provided by Koo et al, 1999. In addition MgTX was also shown to inhibit primary antibody response in non-sensitised animals (secondary antibody response was not affected by MgTX. These latter results are in agreement with the notion that Kv1.3 channels are predominant in resting T lymphocytes and regulate their function, while IKCa1 channels are more important in pre-activated T lymphocytes. Correolide (Koo et al, 1999) and PAP-1 (Schmitz et al, 2005) are novel immunosuppressants which block Kv1.3 channels and are effective in the DTH model. Because the cellular components involved in DTH response are similar to those found in autoimmune diseases and allograft rejection, the results obtained are very promising for the development of Kv1.3 channel blockers as new immunosuppressants.
In the early 1980's a number of compounds were reported to block Kv1.3 channels at micromolar to millimolar concentrations as described by Triggle et al, in “Voltage Gated Ion Channels as Drug Targets” these include classical Kv channel inhibitors such as 4-aminopyridine and tetramethylammonium, and other non specific compounds such as the calcium activated potassium channel blockers quinine and ceteidil, the phenothiazine antipscychotics chloropromazine and trifluoroperazine, the classical calcium channel inhibitors verapamil, diltiazem, nifedipine and nitrendipine, and the beta blocker propranolol.
Also in the 1980's natural products extracted from scorpions, snakes and other marine organisms were found to be potent inhibitors of Kv1.3 channels, these were primarily short peptides (<70 residues) that are stabilised by multiple sulfide bonds. The first of these potent inhibitors was isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus and was named charybdotoxin (ChTX) (Sands et al, 1989), there after screening of other scorpion venoms led to the identification of more potent Kv1.3 blocking toxins, these include margatoxin (MgTX) (Garcia et al, 1993), agitoxin-2 (Garcia et al, 1994), hongotoxin (Koshchak et al, 1998), pandinus imperator toxin 2 (Pi2) (Peter et al, 2001) and orthochirus scrobiculosus (OSK1) (Mouhat et al, 2005) among others. With the exception of OSK1 (300 fold selective over the nearest related channel) none of the scorpion toxins were selective for Kv1.3
One of the most potent and selective Kv1.3 blockers to date, which was extracted from sea anemone is stichodactyla helianthus toxin (Shk) (Pennington et al, 1996) this has been reported for the treatment of autoimmune disease through the blockade of Kv1.3 (U.S. Pat. No. 6,077,680). Shk and its synthetic derivative Shk-Dap22 with improved selectivity profile display pico molar activity (Pennington et al, 1998) however, these peptides proved to have unfavourable properties for further development.
Recently more novel and selective small molecule Kv1.3 channel blockers have been reported for the management of autoimmune disorders. These include the iminodihydroquinolines WIN173173 and CP339818 (Nguyen et al., 1996), the benzhydryl piperidine UK-78,282 (Hanson et al. 1999), correolide (Felix et al., 1999), cyclohexyl-substituted benzamide PAC (U.S. Pat. No. 6,194,458, WO0025774), sulfamidebenzamidoindane (U.S. Pat. No. 6,083,986), Khellinone (Baell et al., 2004), dichloropenylpyrazolopyrimidine (WO-00140231) and psoralens (Wulff et al., 1998, Vennekamp et al., 2004, Schmitz et al., 2005).
Furthermore, the related Kv1.5 channel is expressed in atrial myocytes and is believed to offer therapeutic opportunities for the management of atrial fibrillation for several different reasons (see review of Brendel and Peukert, 2002): (i) There is evidence that Kv1.5 underlies the cardiac ultrarapid delayed rectifier (Kv(ur)) physiological current in humans due to similar biophysical and pharmacological properties (Wang et al., 1993; and Fedida et al., 1993). This has been supported with antisense oligonucleotides to Kv1.5 which have been shown to reduce Kv(ur)) amplitude in human atrial myocytes (Feng et al., 1997). (ii) electrophysiological recordings have demonstrated that Kv(ur)) is selectively expressed in atrial myocytes, and therefore avoids inducing potentially fatal ventricular arrhythmia through interfering with ventricular repolarisation (Amos et al., 1996; Li et al., 1996; and Nattel, 2002). (iii) Inhibiting Kv(ur)) in atrial fibrillation-type human atrial myocytes prolonged the action potential duration compared to normal healthy human atrial myocytes (Courtemanche et al., 1999). (iv) Prolonging the action potential duration by selectively inhibiting Kv1.5 could present safer pharmacological interventions for protecting against atrial re-entrant arrhythmias such as atrial fibrillation and atrial flutter compared to traditional class III antiarrythmics, by prolonging the atrial refractory period while leaving ventricular refractoriness unaltered (Nattel et al., 1999, Knobloch et al., 2002; and Wirth et al., 2003). Class III antiarrythmics have been widely reported as a preferred method for treating cardiac arrhythmias (Colatsky et al., 1990).
Drugs that maintain the sinus rhythm long-term without proarrhythmic or other side effects are highly desirable and not currently available. Traditional and novel class III antiarrythmic potassium channel blockers have been reported to have a mechanism of action by directly modulating Kv1.5 or Kv(ur). The known class III antiarrythmics ambasilide (Feng et al., 1997), quinidine (Wang et al., 1995), clofilium (Malayev et al., 1995) and bertosamil (Godreau et al., 2002) have all been reported as potassium channel blockers of Kv(ur)) in human atrial myocytes. The novel benzopyran derivative, NIP-142, blocks Kv1.5 channels, prolongs the atrial refractory period and terminates atrial fibrillation and flutter in in vivo canine models (Matsuda et al., 2001), and S9947 inhibited Kv1.5 stably expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells and Kv(ur)) in native rat and human cardiac myocytes (Bachmann et al., 2001). Elsewhere, other novel potassium channel modulators which target Kv1.5 or Kv(ur)) have been described for the treatment of cardiac arrhythmias, these include biphenyls (Peukert et al 2003), thiophene carboxylic acid amides (WO0248131), bisaryl derivatives (WO0244137, WO0246162), carbonamide derivatives (WO0100573, WO0125189) anthranillic acid amides (WO2002100825, WO02088073, WO02087568), dihydropyrimidines (WO0140231), cycloalkylamine derivatives (WO2005018635), isoquionolines (WO2005030791), quinolines (WO2005030792), imidazopyrazines (WO205034837), benzopyranols (WO2005037780), isoquinolinones (WO2005046578), cycloakyl derivatives (WO03063797), indane derivatives (WO0146155 WO9804521), tetralin benzocycloheptane derivatives (WO9937607), thiazolidone and metathiazanone derivatives (WO9962891), benzamide derivatives (WO0025774), isoquinoline derivatives (WO0224655), pyridazinone derivatives (WO9818475 WO9818476), chroman derivatives (WO9804542), benzopyran derivatives (WO0121610, WO03000675, WO0121609, WO0125224, WO02064581), benzoxazine derivatives (WO0012492), and the novel compound A1998 purified from Ocean material (Xu & Xu, 2000).
Sulfonamides have been reported to be useful as inhibitors of 11-beta-hydroxysteroid dehydrogenase type1, CCR5, H3 receptor and mitotic kinesins amongst others.
1,4-substituted aryl tertiary sulfonamides, wherein position 4 is substituted with an amide have been claimed as inhibitors of 11-betahydroxysteroid dehydrogenase type1, for the treatment and prevention of hyperglycemia in diseases such as type-2 diabetes (WO2004065351).
1,4-substituted aryl tertiary sulfonamides, wherein position 4 is optionally substituted with substituted alky, alkoxyamino, sulfonyl, acyl, alkoxy carbonyl or aminocarbonyl have been claimed as inhibitors of mitotic kinesins as effective anti cancer agents (WO2007056078).
1,4-substituted aryl tertiary sulfonamides, wherein the sulfonamide N is linked to lower alkyl, lower alkenyl, cycloalkyl or cycloalkyl and position 4 is optionally substituted with carbonyl, alkyl or secondary alcohol have been claimed as class III antiarrythmics (U.S. Pat. No. 4,876,262).
1,4-substituted aryl tertiary sulfonamides, wherein position 4 is optionally substituted with alkyl, carbonyl or sulfinyl group have been claimed as inhibitors of CCR5 for the treatment of HIV infection and other CCR5 mediated disorders (WO2000454974).
1,4-substituted aryl tertiary sulfonamides have been claimed as herbicides (WO200690792).
1,4-substituted aryl tertiary sulfonamides, wherein position 4 is substituted with an amide have been claimed as inhibitors of histamine H3 receptor for the treatment of obesity, cognitive deficiencies, narcolepsy and other H3 receptor related diseases (WO200756078)
1,4-aryl tertiary methylsulfonamides, wherein position 4 is substituted with cyclic amides and the sulfonamide N is linked to methylnaphthalene have been reported to be potent inhibitors of Factor Xa and show strong anti-thrombotic effects (Wenrong et al, 2003)
1,4-substituted aryl tertiary phenylsulfonamides, wherein position 4 is substituted with a secondary alcohol are reported to inhibit the human pregnane receptor (PXR) which plays a key role in the regulation of regulation of metabolism and excretion of potentially harmful compounds. This is desirable as a potential way to control up-regulation of drug metabolism pathways during the therapeutic treatment of disease (Xue et al, 2007)
It has now surprisingly been found that compounds of general formula (I) set out below act as inhibitors of potassium channels. These compounds are particularly useful for inhibiting the potassium channel Kv1.3 and treating diseases associated with the inhibition of the potassium channel Kv1.3. This invention is not limited to treating diseases mediated by Kv1.3, the compounds also being useful to treat other diseases which require potassium channel inhibition (Triggle et al, 2006). Thus, in a first aspect, the present invention provides a compound of formula (I)
or its salts or pharmaceutically acceptable derivatives wherein;R1 is selected from the group consisting of optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted heteroaryl;R2 is selected from the group consisting of optionally substituted acyl, optionally substituted sulfonyl and optionally substituted sulfamoyl;R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino carbonyl, optionally substituted amino sulfonyl or nitrile;X1 is selected from a group consisting of a chemical bond, CR7R8, C(═O), C(═NH), NR9, NHC(═O), and SO2 wherein;R7 and R8 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl or;R7 and R8 together form an optionally substituted C4-6 cycloalkyl ring;R9 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl;A represents an optionally substituted saturated or partially saturated 4-7 membered ring with the general formula:
or is selected from:

For each occurrence;
X2 is CH or N;
X3 is CH2, CH(R5a), C(R5a)(R5b), NH, N(R5c), O or S;
X4 is independently selected from C(═O), CH2, CH(R4a) or C(R4a)(R4b);
R4a and Rob for each occurrence is independently halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;R5a and R5b for each occurrence is independently, halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;R5c is optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;n=1 or 2
In one embodiment the invention provides a compound of the following formula:
or its salts or pharmaceutically acceptable derivatives wherein;R1 is selected from the group consisting of optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted heteroaryl;R2 is selected from the group consisting of optionally substituted acyl, optionally substituted sulfonyl and optionally substituted sulfamoyl;R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino carbonyl, optionally substituted amino sulfonyl or nitrile;X1 is selected from a group consisting of a chemical bond, CR7R8, C(═O), C(═NH), NR9, NHC(═O), and SO2 wherein;R7 and R8 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heteroaryl or;R7 and R8 together form an optionally substituted C4-6 cycloalkyl ring;R9 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl;A represents an optionally substituted saturated or partially saturated 4-7 membered ring with the general formula:
or is selected from:

For each occurrence;
X2 is CH or N;
X3 is C(R5)2, N(R5b), O or S;
X4 is independently selected from C(═O), or C(R4)2;
R4 for each occurrence is independently hydrogen, halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;R5 for each occurrence is independently hydrogen, halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl;R5b is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; andn=1 or 2
As used herein, the following definitions shall apply unless otherwise indicated.
The term “optionally substituted” means that a group may be substituted by one or more substituents which may be the same or different. When otherwise not specified, these substituents are selected from alkyl, cycloalkyl, —O—C(halogen)3 preferably —OCF3, biaryl, carbocyclic aryl, heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino, carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro, sulfamoyl, sulfonyl, sulfinyl, sulfenyl, sulfonamido or urea.
The term “alkyl group” as used herein, is typically a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, preferably 2, 3, 4, or 5 carbon atoms such as a C1-4 alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl and t-butyl. An alkyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one, two or three substituents. Suitable substituents include cyano, halogen, hydroxyl, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, alkanoyl, alkoxy, sulfonamido, nitro, aryl and heteroaryl. The alkyl moiety may also be an “unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety. An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond. An “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
The term “cycloalkyl” as used herein refers to mono- or bicyclic ring or ring systems consisting of 3 to 11 carbon atoms i.e. 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms. The ring system may be a “saturated ring”, which means that the ring does not contain any alkene or alkyne moieties. The cycloalkyl group may also be an “unsaturated ring” which means that it contains at least one alkene or alkyne moiety and provided that the ring system is not aromatic. The cycloalkyl group may be unsubstituted or substituted as defined herein. In addition to the above mentioned substituents one or more ring carbon atoms may also be bonded via a double bond to a group selected from NH, S and O. The cycloalkyl substituent may be bonded via a linker group such as a C1-6 alkyl group, except where the optional substituent is alkyl. One or more hydrogens of the alkyl group in the linker may be replaced by a moiety selected from the group consisting of hydroxy, halo, cyano, amino, thiol, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino and C1-6dialkylamino.
The term “aryl group” as used herein, is typically a C6-10 aryl group such as phenyl or naphthyl. A preferred aryl group is phenyl. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2, 3 or 4 substituents. Suitable substituents include cyano, halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido, N,N-dialkylamino, sulfonamido, aryl and heteroaryl.
The term “carbocyclic” refers to a compound which contains one or more covalently closed ring structures and the atoms forming the backbone of the ring(s) are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings. Carbocyclic groups include both, a “cycloalkyl group”, which means a non-aromatic carbocycle, and a “carbocyclic aryl” group, which means an aromatic carbocycle. The carbocyclic group may optionally be substituted as defined herein.
The term “heterocyclic” or “heterocyclo” as used herein refers to mono- or bicyclic rings or ring systems which include one or more heteroatoms selected from N, S and O. The rings or ring systems include 1 to 6 carbon atoms in addition to the heteroatom(s). The term heterocyclic group includes both, a “heteroalicyclic” group, which means a non-aromatic heterocycle and a “heteroaryl” group, which means an aromatic heterocycle. The heterocyclic moiety may be unsubstituted or substituted as defined herein and the substituents, when positioned adjacent to one another, may combine to form cycloalkyl or heteroalicyclic ring systems for example methylendioxy or difluoromethylendioxy. The heterocyclic substituent may be bonded via a carbon atom or a heteroatom. The heterocyclic group may also include the oxides of nitrogen and sulfur if nitrogen or sulfur are present in the ring.
The term “heteroaryl” as used herein refers to mono- or bicyclic rings or ring systems which include one or more heteroatoms selected from N, S and O. The rings or ring systems include 3 to 13 carbon atoms in addition to the heteroatom(s) and contain at least one aromatic ring with a heteroatom. The heteroaryl group may also include the oxides of nitrogen and sulfur if nitrogen or sulfur is present, or an oxo-group respectively. Examples of monocyclic heteroaryl groups include but are not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples of bicyclic heterocycles include but are not limited to indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl and the like. Examples of tricyclic heterocycles include but are not limited to thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl. The heteroaryl group may be unsubstituted or substituted as defined herein. The substituents, when positioned adjacent to one another, may combine to form a cycloalkyl or heteroalicyclic ring for example methylendioxy and difluoromethylendioxy. The heteroaryl substituent may be bonded via a carbon atom or a heteroatom.
The term “arylalkyl”, as used herein, refers to a chemical moiety of formula aryl-C1-6alkyl or C1-6alkyl-aryl as those terms are defined herein.
The term “heteroarylalkyl”, used as herein, refers to a chemical moiety of formula heteroaryl-C1-6alkyl or C1-6alkyl-heteroaryl as those terms are defined herein.
The term “acyl”, as used herein, refers to a chemical moiety of formula (CH2)yC(═O)Rz wherein y is 1-6
The term “amidino” refers to a chemical moiety with the formula (CH2)yC(═NH)NRzR′z wherein y is 1-6.
The term “amido” refers to both, a “C-amido” group which means a chemical moiety with the formula —C(═O)NRzR′z and a “N-amido” group which means a chemical moiety with the formula —NRzC(═O)R′z.
The term “amine” or “amino” refers to a chemical moiety of formula —NRzR′z. The definition of an amine is also understood to include their N-oxides.
A “cyano” group refers to a chemical moiety of formula —CN.
The term “hydroxy” or “hydroxyl” as used herein, refers to a chemical moiety of formula —OH.
The term “halogen” or “halo” refers to an atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
The term “alkanoyl”, as used herein, refers to a chemical moiety with the formula —C(═O)Rz.
The term “sulfone” or “sulfonyl” refers to a chemical moiety with the formula —S(═O)2Rz.
The term “sulfinyl” refers to a chemical moiety with the formula —S(═O)Rz.
The term “sulfenyl” refers to a chemical moiety with the formula —SRz.
A “sulfamoyl” group refers to a chemical moiety with the formula —N—S(═O)2NRzR′z.
The term “sulfonamido” refers to both an “S-sulfonamido” group which means a chemical moiety with the formula —S(═O)2NRzR′z and an “N-sulfonamido” group which means a chemical moiety with the formula N—S(═O)2R′z.
The term “thiocarbonyl” refers to a chemical moiety with the formula (CH2)yC(═S)Rz wherein y is 1-6.
The term “thio” or “thiol”, as used herein, refers to a chemical moiety of formula —SH.
The term “thioamide” refers to both a “C-thioamido” group which means a chemical moiety with the formula (CH2)yC(═S)NRzR′z and a “N-thioamido” group which means a chemical moiety with the formula (CH2)yNRzC(═S)R′z wherein y is 1-6.
An “urea” group refers to a chemical moiety of formula —NRzC(═O)NRzR′z.
Rz and R′z are independently selected from the group consisting of hydrogen, C1-6alkyl, cycloalkyl, C1-6alkoxy, aryl-C1-6alkyl, aryl and heteroaryl.
One preferred embodiment relates to compounds where A is selected from—
Wherein;X3 is CH2CH(R5a), C(R5a)(R5b), N, N(R5c) or O;R4a and R4b independently represent halogen, hydroxyl, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;R5a and R5b independently represent halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl;R5c represents optionally substituted acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroarylR2 is selected from a group consisting of C(═O)R10, SO2R10 wherein;R10 is selected from NR11R12, optionally substituted aryl, and optionally substituted heteroaryl. More preferably R10 is selected from;NR11R12 or a compound of formula (II), (III), (IV) or (V)
Wherein;R11 and R12 are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl;G, J, L, D, and E are the same or different and each represents C, or N with the proviso that in each instance at least one of G, J, L, D, or E is N;Where R10 is selected from compounds of formula (II), L may also represent O or S andWhere R10 is selected from compounds of formula (III), G may also represent O or S;R13 and R14 are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted C1-3 alkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring;R15, R16, R17, R18, and R19 are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, nitrile, optionally substituted C1-3 alkyl, any of the pairs R15 and R16, or R16 and R17, or R17 and R18, or R18 and R19 or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring;R1 is selected from optionally substituted arylalkyl, and optionally substituted heteroarylalkyl. More preferably R1 is selected from formula (VI)
Wherein;R20, R21, R22, R23 and R24 are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, nitrile, optionally substituted C1-3 alkyl or optionally substituted alkoxy;R25 and R26 are the same or different and each represents hydrogen, hydroxyl, and optionally substituted C1-3 alkylR3 is selected from the group consisting of hydrogen, halogen, hydroxyl, nitrile, or optionally substituted alkyl, preferably hydrogen, halogen or optionally substituted alkyl.X1 is selected from a group consisting of a chemical bond, CH2, and C(═O).
The most preferred compounds of the invention are those of formula (VII):
Wherein;X1 is selected from a group consisting of a chemical bond, CH2, C(═O)X3 is CH2, CH(R5a), CH(R5b), NH, N(R5c) or OX4 is C(═O), CH2, CH(R4a) or C(R4a)(R4b)R3 is selected from the group consisting of hydrogen, halogen, hydroxyl or optionally substituted C1-3 alkylR4a and R4b independently represent halogen, hydroxyl, optionally substituted aryloxy, optionally substituted C1-3 alkyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl. Preferably R4a and R4b independently represent fluoro, optionally substituted methyl, hydroxyl, trifluoromethyl, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzyloxy or optionally substituted oxadiazole.R5a and R5b independently represent halogen, optionally substituted amino, hydroxyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkyl, optionally substituted alkanoyl, optionally substituted cycloalkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl. Preferably R5a and R5b independently represent fluoro, methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenethyl, hydroxyl, substituted hydroxyethyl, hydroxypropyl, hydroxybutyl, optionally substituted phenoxy, optionally substituted benzyloxy, methoxyethyl, methoxypropyl, phenoxyethyl, benzyloxyethyl, acetyl, propionyl, substituted benzoyl, phenacyl, imidazoyl, pyrazoyl, pyridinoyl, oxadiazoloyl, thiazoloyl, acetamide, methylacetamide, dimethylacetamide, ethylacetamide, diethylacetamide, tert-butylacetamide, pyridylacetamide, cyclopropylacetamide, cyclobutylacetamide, cyclopentylacetamide, or cyclohexylacetamide. More preferably R5a and R5b independently represent fluoro, optionally substituted methyl, hydroxyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenoxy, optionally substituted benzyloxy, or thiazoloyl.R5c represents optionally substituted C1-3 alkyl, optionally substituted phenyl and optionally substituted heteroaryl.R10 is selected from;NR11R12 or a compound of formula (II), (III), (IV) or (V)
Wherein;R11 and R12 are the same or different and each represent optionally substituted C1-3 alkyl.
Preferably R11 and R12 are alkyl, preferably CH3;
G, J, L, D, and E are the same or different and each represents C, or N with the proviso that in each instance at least one of G, J, L, D, or E is N;
Where when R10 is formula (II), L may also represent O or S and
Where when R10 is formula (III), G may also represent O or S
R13 and R14 are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted C1-3 alkyl, optionally substituted arylalky, optionally substituted aryl or optionally substituted heteroaryl or may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring. Preferably, R13 and R14 are alkyl, preferably CH3.R15, R16, R17, R18, and R19 are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, nitrile, optionally substituted C1-3 alkyl, any of the pairs R15 and R16, or R16 and R17, or R17 and R18, or R18 and R19 may be taken together to form an optionally substituted saturated or partially saturated 5-7 membered heterocyclic or carbocyclic ring
Preferably R10 is substituted imidazole, substituted pyrazole, substituted pyrrole, substituted oxazole, substituted oxadiazole, substituted thiazole, substituted thiadiazole, substituted pyridine, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted triazine, optionally substituted phenyl, tetrahydrobenzofuran, benzopyran, dihydrobenzodioxin, benzoxazinone, benzooxadiazole, benzodioxole, indoline, indole, indazole, or benzomorpholine. Most preferably R10 is substituted imidazole, substituted pyrazole, substituted pyridine, phenyl, fluorophenyl, cyanophenyl, tetrahydrobenzofuran, benzopyran, dihydrobenzodioxin, benzoxazinone, benzooxadiazole, benzodioxole, indoline, or benzomorpholine;
R20 R21, R22, R23 and R24 are the same or different and each represents hydrogen, halogen, hydroxyl, optionally substituted amino, nitrile, optionally substituted C1-3 alkyl or optionally substituted alkoxy. Preferably R20 R21 R22, R23 and R24 are independently selected from hydrogen, fluoro, chloro or methyln=1 or 2
Particularly preferred compounds of the invention include:    N-(4-Chloro-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(2-Chloro-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(3-Chloro-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(4-Fluoro-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    Naphthalene-2-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    N-Benzyl-3,4-dimethoxy-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    N-Benzyl-4-methyl-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    Thiophene-2-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    Thiophene-3-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    N-Benzyl-4-fluoro-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-2-fluoro-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-3-fluoro-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-4-cyano-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-3-cyano-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-2-cyano-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    N-Benzyl-2-methyl-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-3-methyl-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-3-methoxy-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-3,5-dichloro-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-3-chloro-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(3-Fluoro-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(2-Methoxy-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(3-Methoxy-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(2-Methyl-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(4-Methyl-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-[4-(4-Phenyl-piperazine-1-carbonyl)-phenyl]-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide;    N-[4-(4-Phenyl-piperazine-1-carbonyl)-phenyl]-N-(3-trifluoromethoxy-benzyl)-benzenesulfonamide;    N-(2-Cyano-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(4-Cyano-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    2,2-Dimethyl-chroman-6-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    N-Benzyl-4-nitro-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    Furan-2-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    N-Benzyl-N-[3-methyl-4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-N-[2-fluoro-4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-N-[3-methoxy-4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-N-[4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-N-[4-(2,6-dimethyl-morpholine-4-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-N-[4-(piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-4-ethyl-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-N-[4-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-Benzyl-N-[4-(4-benzyl-4-hydroxy-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(2,3-Dimethoxy-benzyl)-N-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(4-Chloro-benzyl)-N-[4-(3-p-tolyl-piperidine-1-carbonyl)-phenyl]-benzenesulfonamide;    N-(4-Chloro-benzyl)-N-{4-[3-(4-methoxy-phenyl)-piperidine-1-carbonyl]-phenyl}-benzenesulfonamide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[2-methyl-4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[2-fluoro-4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-methyl-benzyl)-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (3-fluoro-benzyl)-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (3-methoxy-benzyl)-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-{4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carbonyl]-phenyl}-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3-phenyl-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3-phenoxy-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(3-phenyl-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-{4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carbonyl]-phenyl}-amide;    1,3-Dimethyl-1H-pyrazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    2,3-Dimethyl-3H-imidazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    2,4-Dimethyl-thiazole-5-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(4-phenyl-piperazine-1-ylmethyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[2-fluoro-4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-amide;    N-Benzyl-N-[4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-dimethylsulfamide;    N-Benzyl-N-[4-(2-phenyl-morpholine-4-carbonyl)-3-fluorophenyl]-dimethylsulfamide;    N-(4-Fluoro)benzyl-N-[4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-dimethylsulfamide;    4-{4-[Benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzoyl}-2-phenyl-piperazine-1-carboxylic acid tert-butyl ester;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-{4-[3-(4-fluoro-phenyl)-pyrrolidine-1-carbonyl]-phenyl}-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(piperidine-1-carbonyl)-phenyl]-amide;    N-Benzyl-N-{4-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-phenyl}-dimethylsulfamide;    N-Benzyl-N-{4-[3-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carbonyl]-phenyl}-diemthylsulfamide;    N-Benzyl-N-[4-(3-benzyloxy-pyrrolidine-1-carbonyl)-phenyl]-diemthylsulfamide;    N-Benzyl-N-[4-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-phenyl]-diemthylsulfamide;    N-Benzyl-N-[4-(4-phenoxy-piperidine-1-carbonyl)-phenyl]-diemthylsulfamide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(3-methyl-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-{4-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-phenyl}-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(4-cyclohexylmethyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(4-methyl-3-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(4-thiazol-2-yl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(3-trifluoromethyl-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(4,4-difluoro-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid benzyl-[4-(3-fluoro-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-[4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-amide;    2-Methyl-2H-pyrazole-3-sulfonic acid benzyl-[4-(2-phenyl-morpholine-4-carbonyl)-phenyl]-amide;    1-Methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-[4-(piperidine-1-carbonyl)-phenyl]-amide;    Pyridine-3-sulfonic acid (4-chloro-benzyl)-[4-(piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-[4-(3-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    2-Methyl-2H-pyrazole-3-sulfonic acid benzyl-[4-(3-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-pyrazole-3-sulfonic acid benzyl-[4-(4-methyl-3-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    2-Methyl-2H-pyrazole-3-sulfonic acid benzyl-[4-(4-methyl-3-phenyl-piperazine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3-methyl-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (3-chloro-benzyl)-[4-(piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-fluoro-benzyl)-[4-(3-methyl-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-methyl-benzyl)-[4-(3-methyl-piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (3,4-dichloro-benzyl)-[4-(piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (3-chloro-4-fluoro-benzyl)-[4-(piperidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(2-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide;    1-Methyl-1H-imidazole-4-sulfonic acid (4-chloro-benzyl)-[4-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenyl]-amide;and pharmaceutically acceptable salts thereof.
As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, arylalkyl amines or heterocyclic amines.
The compounds of the invention may contain one or more chiral centres. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereo isomers of the compounds shown, including racemic and non racemic mixtures and pure enantiomers and/or diastereoisomers.
As discussed herein, the compounds of the invention are useful in the treatment of various conditions. Thus, in a second aspect, the present invention provides a compound of formula (I) as defined herein for use in medicine. Preferably the compound is used to prevent or treat conditions which require inhibition of potassium channels, such as immunological disorders, including psoriasis, rheumatoid arthritis and multiple sclerosis.
In a further aspect the present invention provides a pharmaceutical formulation comprising at least one compound of formula I or as defined herein and optionally one or more excipients, carriers or diluents.
The compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose. Such a unit may be adapted to provide 5-100 mg/day of the compound, preferably either 5-15 mg/day, 10-30 mg/day, 25-50 mg/day 40-80 mg/day or 60-100 mg/day. For compounds of formula I, doses in the range 100-1000 mg/day are provided, preferably either 100-400 mg/day, 300-600 mg/day or 500-1000 mg/day. Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doctor's discretion.
The compositions of the invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For applications to the eye or other external tissues, for example the mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.
Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The compositions of the invention can be used to treat conditions which require inhibition of potassium channels, for example in the treatment of immunological disorders. Thus, in further aspects, the present invention provides:
(i) A method of treating or preventing a disorder which requires potassium channel inhibition, eg immunological disorders comprising administering to a subject an effective amount of at least one compound of the invention or a pharmaceutical composition of the inventionand(ii) the use of a compound of the invention in the manufacture of a medicament for use in potassium channel inhibition.
In particular, the medicament is for use in the treatment or prevention of psoriasis, rheumatoid arthritis, multiple sclerosis and other immunological disorders and arrythmia
Preferred embodiments of the first aspect apply to all other aspects mutatis mutandis.
The compounds of formula (I) may be prepared by conventional routes, for example those set out in Schemes 1 to 5 shown below.

Compounds of formula (I) in which X1 is C═O, X3, X4, R1 R3, R4, R5 and R10 are defined as above, may be prepared as shown in Scheme 1, from compounds of formula (VIII) where X1 is C═O, A is OH and R1, R3 and R10 are defined as above and amines of formula (IX) where X3, and X4 are defined as above. Typically, this reaction is carried out using a coupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or 2-(7-aza-1H-benztriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (I) in which X3, X4, R1, R3, R4, R5 and R10 are defined as above may be prepared from compounds of formula (VIII) where A is Cl or Br and amines of formula (IX). Typically, this reaction is performed in the presence of a base, for example, triethylamine, utilising standard methods familiar to those skilled in the art such as reaction in solvent such as tetrahydrofuran, acetonitrile or dichloromethane at a range of temperatures from ambient to reflux temperature. Compounds of formula (IX) are known compounds or may be prepared by standard published methods familiar to those skilled in the art.

Compounds of formula (VIII), where A is OH and R1, R3 and R10 are defined as above may be prepared as show in Scheme 2, from compounds of formula (X) where AP is a suitably protected OH group such as a tent-butyl ester and R1, R2, R3 are defined as above, by standard methods familiar to those skilled in the art such as deprotection in the presence of a suitable acid, for example trifluoroacetic acid, utilizing a solvent such as tetrahydrofuran, acetonitrile or dichloromethane, at a range of temperatures from 0° C. to reflux temperature.
Compounds of formula (X) may be prepared from sulfonamides (XII) where R3 and R10) are defined as above, utilizing standard methods familiar to those skilled in the art such as, reaction with an electrophile with the formula R1—Y where R1 is defined as above and Y is Cl or Br in the presence of a base, for example cesium carbonate and a solvent such as tetrahydrofuran, acetonitrile or dichloromethane at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (X) may be prepared from amines (XI) where R1 and R3 are defined as above by standard methods familiar to those skilled in the art such as, reaction with a sulfonyl or sulfamoyl chloride with the formula R10—SO2Cl in the presence of a base, for example pyridine, triethylamine or potassium carbonate and a solvent such as tetrahydrofuran, acetonitrile or dichloromethane, at a range of temperatures from ambient to reflux temperature.
Compounds of formula (XII) are known compounds or may be prepared from compounds of formula (XIII) where R3 is defined as above by standard methods familiar to those skilled in the art, such as reaction with a sulfonyl or sulfamoyl chlorides with the formula R10—SO2Cl in the presence of a base, for example potassium carbonate, triethylamine or pyridine, and a solvent such as dichloromethane, tetrahydrofuran and acetonitrile, at a range of temperatures from ambient to reflux temperature.
Compounds of formula (XI) are known compounds or may be prepared from compounds of formula (XIII) by standard methods familiar to those skilled in the art such as, alkylation with an electrophile with the formula R1—Y where R1 is defined as above and Y is Cl or Br in the presence of a base, for example potassium carbonate, triethylamine or pyridine and a solvent such as dichloromethane, tetrahydrofuran and acetonitrile at a range of temperatures from ambient to reflux temperature. Alternatively, Compounds of formula (XI) may be prepared from compounds of formula (XIII) by standard methods familiar to those skilled in the art, such as reductive amination with an aldehyde with the formula R1—Y where R1 is defined as above and Y is CHO in the presence of a reducing agent, for example sodium triacetoxyborohydride, and a solvent such as dichloromethane, tetrahydrofuran and acetonitrile at a range of temperatures from ambient to reflux temperature. Compounds of formula (XIII) are known compounds or may be prepared by standard methods familiar to those skilled in the art.

Compounds of formula (I) in which R2 is SO2R10 and X1, X3, R1, R3, R4, R5, and R10 are defined as above may be prepared as shown in Scheme 3, from amines of formula (XVI) and sulfonyl or sulfamoyl chlorides with the formula R10—SO2Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods familiar to those skilled in the art such as reaction in solvent, for example tetrahydrofuran, acetonitrile, dichloromethane or toluene, at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (I) may be prepared from compounds of formula (XIV) by standard methods familiar to those skilled in the art such as reaction with an electrophile with the formula R1—Y where R1 is defined as above and Y is Cl or Br in the presence of a base, for example cesium carbonate and a solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene, at a range of temperatures from ambient to reflux temperature.
Compounds of formula (I) in which X1 is CH2, R2 is SO2R10, and X3, X4, R1, R3, R4 R5, and R10 are defined as above may be prepared from compounds of formula (I) wherein X1 is C═O by standard methods familiar to those skilled in the art such as, reduction in the presence of a reducing agent, for example lithium aluminium hydride and a suitable solvent such as tetrahydrofuran or diethylether at a range of temperatures from ambient to reflux temperature.
Compounds of formula (XVI) wherein X1, X3, X4, R1, R3, R4 and R5 are defined as above are either known compounds or may be prepared from amines of formula (XV) by standard methods to those skilled in the art such as, alkylation with an electrophile with the formula R1—Y where R1 is defined as above and Y is Cl or Br in the presence of a base, for example potassium carbonate, triethylamine or pyridine and a solvent such as tetrahydrofuran, dichloromethane or acetonitrile at a range of temperatures from ambient to reflux. Alternatively, compounds of formula (XVI) may be prepared from compounds of formula (XV) by reductive amination with an electrophile with the formula R1—Y where R1 is defined as above and Y is CHO in the presence of a reducing agent such as sodium triacetoxyborohydride utilizing standard methods familiar to those skilled in the art such as reaction in a solvent, for example tetrahydrofuran, dichloromethane or acetonitrile at a range of temperatures from ambient to reflux.
Compounds of formula (XIV) wherein X1, X3, X4, R3, R4, R5 and R10 are defined as above are known compounds or may be prepared from amines of formula (XV) and sulfonyl or sulfamoyl chlorides with the formula R10—SO2Cl in the presence of a base, for example triethylamine, diisopropylamine or pyridine, utilizing standard methods familiar to those skilled in the art such as reaction in solvent, for example, tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.

Compounds of formula (XV) in which X1 is C═O, X3, X4, R3, R4 and R5 are defined as above, are known compounds or may be prepared as shown in Scheme 4, from compounds of formula (XIX) wherein X1 is C═O, A is OH and R3 is defined as above, and compounds of formula (IX) together with a coupling reagent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or 2-(7-aza-1H-benztriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) utilising standard methods familiar to those skilled in the art such as reaction in solvent, for example tetrahydrofuran, acetonitrile or dimethylformamide at range of temperatures from ambient to reflux temperature.
Compounds of formula (XV) in which X1 is CH2, X3, X4, R3, R4 and R5 are defined as above are known compounds or may be prepared from compounds of formula (XIX) wherein X1 is CH2 and A is a leaving group such as Cl or Br and compounds of formula (IX) by standard methods familiar to those skilled in the art such as alkylation in the presence of a base, for example triethylamine, diisopropylamine or pyridine and a solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.
Compounds of formula (XV) in which X1 is CH2, X3, X4, R1, R3, R4 and R5 are defined as above, may be prepared from compounds of formula (XIX) wherein X1 is C═O and A is H and compounds of formula (IX) by standard methods familiar to those skilled in the art such as reductive amination in the presence of a reducing agent, for example sodium triacetoxyborohydride and a solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature. Alternatively, compounds of formula (XV) in which X1 is CH2, X4 is CH2, X3, R1, R3, R4, R5 and R6 are defined as above, may be prepared from compounds of formula (XV) wherein X1 is C═O by standard methods familiar to those skilled in the art such as reduction in the presence of a reducing agent, for example lithium aluminium hydride and a solvent such as tetrahydrofuran or diethylether at a range of temperatures from ambient to reflux.
Compounds of formula (XV) in which X1 is a chemical bond, CH2 or C(═O) and X3, X4, R3, R4 and R5 are defined are known compounds or may be prepared as shown in scheme 4, from compounds of formula (XVII) where X1 is a chemical bond, CH2 or C(═O) by standard methods familiar to those skilled in the art such as reduction using a reducing agent, for example tin(II)chloride and a suitable solvent such as ethyl alcohol at a range of temperatures from ambient to reflux.
Compounds of formula (XVII) in which X1 is CH2 or C(═O) may be synthesised from nitro compounds (XVIII) in which A is a leaving group such as Cl or Br and compounds of formula (IX) by standard methods familiar to those skilled in the art using a base such as pyridine, triethylamine or potassium carbonate and a suitable solvent such as tetrahydrofuran, acetonitrile, dichloromethane or toluene at a range of temperatures from ambient to reflux temperature.

Compounds of formula (XVII) in which X1 is a chemical bond X3, X4, R3, R4 and R5 are defined as above are known compounds or may be prepared, from compounds of formula (XX) and compounds of formula (IX) utilizing a base such as N-methyl morpholine by standard methods familiar to those skilled in the art, for example reaction in a solvent such as dichloromethane, acetonitrile, tetrahydrofuran or N,N-dimethylformamide at a range of temperatures from ambient to reflux. Alternatively, compounds of formula (XVII) in which X1 is a chemical bond, may be prepared from compounds of formula (XXII) by standard methods familiar to those skilled in the art such as reaction with electrophiles of formula (XXI) wherein Y is Cl or Br in the presence of a base, for example pyridine or triethylamine and a suitable solvent such as dichloromethane, acetonitrile or tetrahydrofuran at a range of temperatures from ambient to reflux. Compounds of formula (XX), (XXII) and (XXI) are known compounds or may be prepared by known methods familiar to those skilled in the art.
The compounds of the invention are found to be inhibitors of potassium channels (Kv) and are therefore therapeutically useful. Such compounds are believed to be novel and the present invention also provides for these compounds. The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds. Many of the starting materials referred to in the reactions described above are available from commercial sources or can be made by methods cited in the literature references.